Overview
For patients with diabetes mellitus (DM), increased blood sugar can damage the blood vessels of the retina eventually causing systemic complications such as diabetic retinopathy (DR). Progression of DR to advanced stages may prompt the development of diabetic macular edema (DME), the leading cause of vision loss in patients living with diabetes.1

 

Diabetic Macular Edema
Diabetic macular edema is an important vision-threatening manifestation of DR. It is assessed separately from the other stages of DR since DME can be observed at any severity level of DR and can run an independent course.

According to the International Classification, DME has been defined and classified based on clinical examination or results of retinal photography according to its proximity to the fovea. Patients found to have retinal thickening in the macula not involving the central subfield zone (1-mm in diameter) is classified as non-center-involving DME. Those with retinal thickening in the macula that involves the central subfield zone of 1 mm in diameter are classified as center-involving DME (Table 1).2

 

 

Image 1. Fundus photograph showing moderate macular edema2

Image from: Wong TY, et al. Guidelines on Diabetic Eye Care. American Academy of Ophthalmology. 2018 October; 125(10):1608-1622.

 

Pathogenesis
The pathophysiology of DME is considered multi-factorial and complex involving different pathways activated by hyperglycemia. Breakdown of the blood-retinal barrier (BRB) is the common pathway leading to DME and other exudative retinal conditions. Impairment in the integrity of the BRB leads to leakage of plasma solutes into the interstitial spaces which in turn causes edema via increased osmotic pressure. Subsequently, fluid accumulates in different spaces within and underneath the retina.2

Disruption of the BRB is caused by various triggers. It may result from the release of inflammatory cytokines and growth factors in the state of chronic hyperglycemia. Implicated factors include vascular endothelial growth factor-A (VEGF-A), placenta growth factor (PlGF), interleukin (IL) 8, IL-6, IL-1β, TNF-α and matrix metalloproteinases.2

During the state of hyperglycemia, diacyglycerol increases and activates protein kinase C (PKC), the ß isoform of which can be found in high concentrations in the retina. Activated PKC-ß mediates retinal vascular permeability which leads to further BRB impairment.2

Another effect of hyperglycemia is the non-enzymatic glycation of plasma proteins and the basal lamina leading to the production of advanced glycation end products (AGEs). These AGEs subsequently increase the transcription of inflammatory cytokines and VGEF that collectively cause disruption of the BRB seen in DME.2

 

Risk Factors

Having hypertension, established cardiovascular disease, advanced diabetic retinopathy, and proliferative diabetic retinopathy have been associated with the development of DME. Although correlations exist between these risk factors and DME, controlling blood glucose, blood pressure, and lipid levels had not shown benefits in modifying DME prognosis.1

 

Symptoms

Having blurry or wavy vision near or in the center of the field of vision is the primary symptom of DME. Color vision may also appear washed out or faded, while some patients may have difficulty reading. These symptoms may not be apparent initially and are noticed only when the condition is well advanced.3, 4

 

Screening

Slit lamp evaluation and stereo fundus photography are primarily used in the evaluation of DME. Fundus photography is a useful way of recording disease activity and determining the detailed severity of the disease. It likewise provides a feasible method of examination for countries with low or intermediate resources. However, there are multiple new modalities that have been developed and used in evaluating DME.

Optical coherence tomography (OCT) is presently regarded as the most sensitive method in detection and assessment of DME. This high-resolution imaging modality is useful in determining the thickness of the retina. However, due to the high costs of this imaging equipment and the required training of ophthalmologists, OCT is only considered feasible for countries with high resources.2

Fluorescein angiography, although not required to diagnose DME, can be used as guide in evaluating retinal non-perfusion area, presence of neovascularization and microaneurysms or macular capillary nonperfusion in DME.2

 

Management

Treatment of DME is focused on reestablishing BRB and modulating inflammatory as well as angiogenic factors. Laser photocoagulation has been one of the mainstays for DME treatment offering improved visual acuity in some patients. The Early Treatment Diabetic Retinopathy Study (ETDRS) has been shown to reduce vision loss for patients with clinically significant macular edema. Although macular laser photocoagulation is a major treatment modality for clinically significant macular edema, it is not curative and many cases are refractive to the laser therapies.2

In the recent years, intravitreal administration of anti-VEGF agents has become the standard care with favorable outcomes in preventing vision loss among patients with DME. For patients who demonstrate center-involving DME and associated vision loss, intravitreal anti-VEGF treatment with ranibizumab, bevacizumab or aflibercept therapy can be considered.2,5

For patients with persistent retinal thickening despite anti-VEGF therapy, consider laser treatment after 24 weeks. Another option is treatment with intravitreal triamcinolone especially in pseudophakic eyes. If the patient has concomitant glaucoma, ocular hypertension, or is a steroid responder, intravitreal triamcinolone should be given with caution and only if intraocular pressure can be monitored during the course of therapy.

Vitrectomy may be considered for patients who do not respond to medical therapy and in cases when there is evidence of vitreoretinal traction. This procedure has also been postulated to improve DME even in the absence of vitreoretinal traction by increasing oxygenation of the vitreous cavity.

 

References:
1. Bahrami, B., Zhu, M., Hong, T. et al. Diabetic macular oedema: pathophysiology, management challenges and treatment resistance. Diabetologia. 2016; 59: 1594–1608. doi: https://doi.org/10.1007/s00125-016-3974-8

2. Wong TY, et al. Guidelines on Diabetic Eye Care. American Academy of Ophthalmology. 2018 October; 125(10):1608-1622.

3. National Institute of Health. At a glance: Macular Edema [Internet]. 2018 July 8 [cited 28 July 2020]. Available from: https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseas....

4. American Academy of Ophthalmology. Macular Edema Symptoms [Internet]. 2019 December 17 [cited 28 July 2020]. Available from: https://www.aao.org/eye-health/diseases/macular-edema-symptoms.

5. Gonzales-Cortes. Treatment of Diabetic Macular Edema: shifting paradigms. Medicina Universitaria. 2015;17(69):243-247.

 

 

 


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